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The strip focuses on the adventures of a creative little boy, Liō, who lives with his father (unnamed in the strip) and his pets. Liō's mother is deceased.[1] It is currently unknown how she died. The setting of the story varies from Liō's house to his school and the general outside world. The time period appears to be contemporary, except for an episode set in the year 2101, when Liō is in his nineties but still very much capable of mischief.

The story is told visually, with little or no dialogue. Gags frequently involve the supernatural, alien invasion or mass destruction of many sorts, creating a surreal, disturbing atmosphere. Some of the strip's recurring themes involve Liō getting even with grade-school bullies, helping animals (most of which are non-anthropomorphic but display obvious intelligence) defend themselves against humans or their predators, and performing mad scientist style experiments. He is often seen using robots that he constructs himself for causing mischief. Another recurring gag in the strip is parody of other famous comic strips, including Cathy, For Better or For Worse, Garfield, Zits, Calvin and Hobbes, Blondie, Peanuts, Pearls Before Swine, The Family Circus and Berkeley Breathed's strips.

In addition to Liō, the strip only has one other major character, Liō's unnamed father. He is frequently shown to be the subject of Liō's pranks, and sometimes he has to get his son out of difficult situations. When he watched a news report of an alien invasion, he gave Liō a spanking for apparently having piloted the alien ship and parking it in the backyard (dated at 2007/02/09). On the other hand, one day when the boy came home from school dejected because a drawing he created had horrified the faculty, Dad proudly hung up the piece of art on the refrigerator, giving his son much-needed comfort and joy (dated 2009/03/15). Quite often, father and son prove that they really love each other, no matter what.[1]

Liō has at least five companion animals:

Fido, a spider who has helped him cheat on tests.

Cybil, a white cat who has unique methods for getting Liō to feed her. She looks sweet and innocent but is not.

Eva Rose, a violent girl with bangs that cover her eyes and an interest on surgeries and autopsies. Liō has a crush on her. She does not return the feeling and is often quite violent towards him or his expressions of love. This does not sway Liō in the slightest, except maybe to make him even more determined in his quest to win her love.

Bubbles, Lio's wide-eyed infant cousin who is scared of nothing and comes up with devious plots.

While it may seem that all the strips are from Liō's imagination, Tatulli has stated that all events in the strip actually happen to Liō,[2] though most of the time others turn a blind eye to it, unlike the other-worldly situations in Calvin and Hobbes.

Another notable aspect of Liō (reminiscent of such strips as The Little King, Henry and Ferd'nand) is its general lack of dialogue, though there are occasional vocalizations (such as "Eeck!" or "Aggh!") and there are labels on certain objects to make the gags more obvious. One-time characters have sometimes spoken, and characters in some of the parodies have had dialogue even when Liō himself is silent.

An October 23, 2007 article in Variety revealed that the strip had been optioned for a live-action feature film by producer David Kirschner.[6] But as of 2014 there has been no word if the film started production.